Acute kidney injury (AKI) is a common and devastating clinical problem. Despite the morbidity, mortality, and financial drain associated, there are no established therapies outside of dialytic treatment. Hypotension or sepsis with associated ischemia is the most common cause of human AKI, and the ensuing injury to the kidney tubular epithelium is of central importance to the pathophysiology of AKI. Recent work has identified adaptive responses in the tubular epithelium to cope with ischemia-reperfusion injury (IRI). Unfortunately, these adaptive responses are often suboptimal. There is a critical need to identify how adaptive responses are regulated in AKI so that therapeutic interventions to prevent and treat AKI can be developed. Hypoxia inducible factor-1 (HIF-1) is a transcription factor regarded as the most significant mediator of cellular adaptive responses to hypoxic insult. There is emerging evidence that the transmembrane glycoprotein mucin 1 (human MUC1 or rodent Muc1) expressed on the apical surface of kidney epithelia plays a novel and important role in enhancing HIF-1 activity. MUC1 is cleaved at the cell surface and its cytoplasmic tail is targeted to the nucleus where it binds and stabilizes HIF-1? and thereby transactivates the HIF-1 protective pathway. We have strong preliminary data suggesting that genetic deletion of Muc1 from mouse tubular epithelial cells exacerbates damage from IRI, limits adaptive HIF-1 responses, alters tubular metabolism, and inhibits recovery. The central hypothesis of this application is that epithelial Muc1 is an important modulator of tubular epithelial adaptive and regenerative responses during AKI. The specific aims are: (1) To determine if Muc1 protects the kidney during ischemia-reperfusion injury (IRI) by enhancing the HIF-1? protective pathway. We will test the hypothesis that Muc1 is protective in IRI through transactivation of the HIF-1 protective pathway. Experiments are designed to determine if Muc1 is protective in a mouse model of IRI, and if this protection results through transduction of the HIF-1 protective pathway by Muc1 stabilization of HIF-1?. (2) To determine if increased levels of Muc1 in the kidney enhances protection during IRI. As female mice are more resistant to IRI than males, and females express more Muc1 in the proximal tubule than male mice, we will test the hypothesis that increased levels of Muc1 in the kidney make the kidney more resistant to IRI. Sensitivity of kidneys to bilateral IRI will be assessed 24 h after varying times of ischemia using male and female mice either (i) overexpressing Muc1/MUC1 (Tg-MUC1), (ii) with reduced Muc1 levels (heterozygotes Muc1-/+), or (iii) injected with a PPAR? agonist to induce Muc1 expression. The overall goal of our proposed experiment is to understand the mechanism of Muc1 protection of the kidney during IRI and determine whether increased levels of Muc1 are protective. This information can be used to design therapies to induce MUC1 and limit the severity of AKI.